PROTEIN STRUCTURE INITIATIVE (STRUCTURAL GENOMICS)

Release Date:  June 22, 1999

PA NUMBER:  PA-99-116

National Institute of General Medical Sciences
National Center for Research Resources
National Institute of Environmental Health Sciences

THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  IT INCLUDES
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA.

PURPOSE

The purpose of this program announcement (PA) is to encourage research on the
development of methodology and technology underpinning the emerging field of
structural genomics, whose goal is the understanding of protein structural
families, structural folds, and the relation of structure and function. 
Projects related to high throughput structure determination by X-ray
crystallography and/or NMR, as well as those addressing other constituent
tasks of structural genomics, are relevant to this PA.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS led national
activity for setting priority areas.  This Program Announcement (PA), Protein
Structure Initiative (Structural Genomics), is related to one or more of the
priority areas.  Potential applicants may obtain a copy of "Healthy People
2000" at http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and non-
profit organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of state and local governments, and eligible
agencies of the Federal government.  Foreign institutions are not eligible for
program project (P01) grants.  Racial/ethnic minority individuals, women, and
persons with disabilities are encouraged to apply as principal investigators.

MECHANISM OF SUPPORT

Support of this program will be through the individual research project grants
(R01) and program project grants (P01).  Applications will be assigned
according to standard NIH referral guidelines.  Applicants proposing to submit
program project (P01) applications must contact program staff listed below. 
Depending upon the institute to which the P01 application is assigned, it must
meet either the NIGMS requirements as stated in the NIH Guide for Grants and
Contracts, Vol. 25, No. 10, March 29, 1996, available at:
http://www.nih.gov/nigms/funding/pa/prog_proj_grants.html or the NIEHS
guidelines as available at http://www.niehs.nih.gov/dert/programs/p01.htm. 
Regardless of the mechanism proposed, potential applicants are strongly urged
to contact the program staff listed under INQUIRIES for guidance in the
preparation of the application.  Responsibility for the planning, direction,
and execution of the proposed project will be solely that of the applicant. 
The total project period for an application submitted in response to this PA
may not exceed five years.

Individual Research Project (R01) Grants Requesting Less Than $250,000 Direct
Costs Per Year.

For the individual research project grant (R01) mechanism, specific
application instructions have been modified to reflect "MODULAR GRANT" and
"JUST-IN-TIME" streamlining efforts being examined by the NIH.  The modular
grant concept establishes specific modules in which direct costs may be
requested as well as a maximum level for requested budgets.  Only limited
budgetary information is required under this approach.  The just-in-time
concept allows applicants to submit certain information only when there is a
possibility for an award.  It is anticipated that these changes will reduce
the administrative burden for the applicants, reviewers and Institute staff. 
Complete and detailed instructions and information on Modular Grants can be
found at http://www.nih.gov/grants/funding/modular/modular.htm.

R01 applications that request more than $250,000 direct costs per year should
follow the instructions in the PHS Form 398.

RESEARCH OBJECTIVES

Following the completion of the sequence of the human genome, a crucial step
in understanding living systems is the determination of the structure and
function of the entire set of gene products.  Data from the genome project
have led to comparative protein sequence analyses and numerous efforts to
develop methodologies for the identification of protein families.  Utilization
of these computational analyses with structural determinations by X-ray
crystallography and/or NMR techniques to study protein structural families
constitutes the new field of structural genomics and is the goal of the NIGMS
Protein Structure Initiative (PSI).  These studies should lead to an
understanding of structure/function relationships and the ability to obtain
structural models of all proteins identified by genomics.  This project will
require the determination of a large number (perhaps 10,000) of protein
structures in a high throughput mode.  Recent and anticipated technological
developments in protein structural determinations make this formidable task
feasible.  The availability of comparative sequence analyses and
methodological improvements now make such a large-scale structural project
appropriate.

Three recent workshops sponsored by NIGMS have focussed on the practicality,
constituent tasks, goals, and planning of this project.  There was general
agreement on technical feasibility due to advances in the development of high
throughput expression systems, protein purification, and sample preparation
(crystallization for X-ray and isotopic labeling for NMR).  All of these can
likely be organized on the large scale required.  Methods for the structure
determination of proteins have also improved significantly in recent years. 
The identification of protein families and target selection proved to be the
most controversial topic and was the focus of the third workshop.  A summary
of these meetings can be found on the NIGMS web site at
http://www.nih.gov/nigms/funding/psi.html.  Following the workshops and
discussions by the National Advisory General Medical Sciences Council, it was
concluded that the necessary tasks for the PSI project are feasible and that
the goal of this initiative is an important scientific endeavor.  The
resulting basis set of protein structures and structure folds will be crucial
in understanding protein structure and evolution, will contribute to the
solution of the protein folding problem, and will provide insights into the
relationship of structure and function.

These discussions have led to the development of this support program for
research on the development of methodology and technology for the constituent
tasks of structural genomics and the PSI.  The scope of this PA includes all
the computational and experimental facets described above.  These applications
must directly address one or more of the constituent tasks of structural
genomics and lead to likely improvements in the efficiency of the subsequent
large scale program for structural determination in a high throughput mode.

Grantees in the PSI program will be expected to attend an annual meeting at
the NIH to discuss their progress and results.

Summary

The purpose of this program announcement is to stimulate research projects on
the development of methodology and technology related to structural
determinations in a high throughput mode and the other constituent tasks of
structural genomics.  This research is crucial for the subsequent development
of a structural genomics research program and a structural inventory of
proteins in living systems.

There are two initiatives related to this one:

1.  A similar program for structural genomics methodology and technology
development for Small Business Innovation Research/Small Business Technology
Transfer (SBIR/STTR) applications.  The SBIR/STTR Program Announcement is
available at:  http://www.nih.gov/grants/guide/pa-files/PA-99-117.html

2.  Projects to serve as pilots to examine the best approach to integrated PSI
(Structural Genomics) programs.  These applications should include all the
constituent parts of the overall PSI project.  These pilots will be supported
as research centers and the Request for Applications (RFA) for this program
was published on June 3, 1999.  The RFA is available at the following URL:
http://www.nih.gov/grants/guide/rfa-files/RFA-GM-99-009.html

NIEHS is partnering with NIGMS and NCRR on this initiative because the
Institute is committed to enhance the understanding of the function of genes
and gene products that are essential in the cellular response to environmental
insults.  To accomplish this goal the NIEHS has implemented the Environmental
Genome Project  (http://www.niehs.nih.gov/envgenom/home.htm).  Its major goal
is to characterize specific genetic variations, or polymorphisms, that
contribute to either susceptibility or resistance to environmentally induced
diseases.  Understanding the biological significance of the observed
polymorphisms will require detail analysis of the structure/function
relationships of the gene products coded by the relevant genes.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
4/98) and will be accepted at the standard application deadlines as indicated
in the application kit.  Application kits are available at most institutional
offices of sponsored research and may be obtained from the Division of
Extramural Outreach and Information Resources, National Institutes of Health,
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301-710-0267, email:  grantsinfo@nih.gov.

Applicants planning to submit an application requesting $500,000 or more in
direct costs for any year are advised that he or she must contact the
Institute or Center (IC) program staff before submitting the application,
i.e., as plans for the study are being developed.  Furthermore, the
application must obtain agreement from the IC staff that the IC will accept
the application for consideration for award.  Finally, the applicant must
identify, in a cover letter sent with the application, the staff member and
Institute or Center who agreed to accept assignment of the application.

This policy requires an applicant to obtain agreement for acceptance of any
such application and any such subsequent amendment.  Refer to the NIH Guide
for Grants and Contracts, March 20, 1998 at
http://www.nih.gov/grants/guide/notice-files/not98-030.html.

The title and number of the program announcement must be typed on line 2 of
the face page of the application form (i.e., "Protein Structure Initiative,"
PA-99-116) and the YES box must be marked.

Submit a signed, typewritten original of the application, including the
Checklist, and five signed photocopies in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

Budget Instructions for R01 Applications Requesting $250,000 or Less Direct
Costs Per Year - Modular Research Grants Only

The total direct costs must be requested in accordance with the program
guidelines and the modifications made to the standard PHS 398 application
instructions described below:

PHS 398

o  FACE PAGE - Items 7a and 7b should be completed, indicating Direct Costs
(in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular
Total Direct plus Facilities and Administrative (F&A) costs] for the initial
budget period.  Items 8a and 8b should be completed indicating the Direct and
Total Costs for the entire proposed period of support.

o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4
of the PHS 398.  It is not required and will not be accepted with the
application.

o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the
categorical budget table on Form Page 5 of the PHS 398.  It is not required
and will not be accepted with the application.

o  NARRATIVE BUDGET JUSTIFICATION - Use a Modular Grant Budget Narrative page. 
(See http://www.nih.gov/grants/funding/modular/modular.htm for sample pages.) 
At the top of the page, enter the total direct costs requested for each year.

o  Under Personnel, list key project personnel, including their names, percent
of effort, and roles on the project.  No individual salary information should
be provided.  However, the application should use the NIH appropriation
language salary cap and the NIH policy for graduate student compensation in
developing the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct
plus facilities and administrative) for each year, each rounded to the nearest
$1,000.  List the individuals/organizations with whom consortium or
contractual arrangements have been made, the percent effort of key personnel,
and the role on the project.  Indicate whether the collaborating institution
is foreign or domestic.  The total cost for a consortium/ contractual
arrangement is included in the overall requested modular direct cost amount.

Provide an additional narrative budget justification for any variation in the
number of modules requested.

o  BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by
reviewers in the assessment of each individual's qualifications for a specific
role in the proposed project, as well as to evaluate the overall
qualifications of the research team.  A biographical sketch is required for
all key personnel, following the instructions below.  No more than three pages
may be used for each person.  A sample biographical sketch may be viewed at: 
http://www.nih.gov/grants/funding/modular/modular.htm.

- Complete the educational block at the top of the form page;

- List position(s) and honors;

- Provide information, including overall goals and responsibilities, on
research projects ongoing or completed during the last three years.

- List selected peer-reviewed publications, with full citations;

o  CHECKLIST - This page should be completed and submitted with the
application.  If the F&A rate agreement has been established, indicate the
type of agreement and the date.  It is important to identify all exclusions
that were used in the calculation of the F&A costs for the initial budget
period and all future budget years.

o  The applicant should provide the name and phone number of the individual to
contact concerning fiscal and administrative issues if additional information
is necessary following the initial review.

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established NIH referral
guidelines.  Applications will be evaluated for scientific and technical merit
by an appropriate scientific review group convened in accordance with the
standard NIH peer review procedures.  As part of the initial merit review, all
applications will receive a written critique and undergo a process in which
only those applications deemed to have the highest scientific merit, generally
the top half of applications under review, will be discussed, assigned a
priority score, and receive a second level review by the appropriate national
advisory council or board.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  In
the written comments reviewers will be asked to discuss the following aspects
of the application in order to judge the likelihood that the proposed research
will have a substantial impact on the pursuit of these goals.  Each of these
criteria will be addressed and considered in assigning the overall score,
weighting them as appropriate for each application.  Note that the application
does not need to be strong in all categories to be judged likely to have major
scientific impact and thus deserve a high priority score.  For example, an
investigator may propose to carry out important work that by its nature is not
innovative but is essential to move a field forward.

1.  Significance:  Does this study address an important problem?  If the aims
of the application are achieved, how will scientific knowledge be advanced? 
What will be the effect of these studies on the concepts or methods that drive
this field?

2.  Approach:  Are the conceptual framework, design, methods, and analyses
adequately developed, well integrated, and appropriate to the aims of the
project?  Does the applicant acknowledge potential problem areas and consider
alternative tactics?

3.  Innovation:  Does the project employ novel concepts, approaches or method? 
Are the aims original and innovative?  Does the project challenge existing
paradigms or develop new methodologies or technologies?

4.  Investigator:  Is the investigator appropriately trained and well suited
to carry out this work?  Is the work proposed appropriate to the experience
level of the principal investigator and other researchers (if any)?

5.  Environment:  Does the scientific environment in which the work will be
done contribute to the probability of success?  Do the proposed experiments
take advantage of unique features of the scientific environment or employ
useful collaborative arrangements?  Is there evidence of institutional
support?

In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:

o  The reasonableness of the proposed budget and duration in relation to the
proposed research.

o  The adequacy of the proposed protection for humans, animals or the
environment, to the extent they may be adversely affected by the project
proposed in the application.

The initial review group will also examine the provisions for the protection
of the research environment.

AWARD CRITERIA

Applications will compete for available funds with all other approved
applications assigned to that Institute or Center.  The following will be
considered in making funding decisions:

o  quality of the proposed project as determined by peer review;

o  program priority of research in the area of the program announcement and
other areas of Institute interest.  Particular attention will be given to
whether or not the development of methods and technologies described in the
application are likely to increase high throughput structure determination and
provide the underpinning for structural genomics projects;

o  availability of funds; and

o  plans for rapid dissemination of the results and, if applicable, rapid
deposition and release of all protein coordinates into the Protein Data Bank,
i.e., holds on release are not permitted.

INQUIRIES

Inquiries are encouraged.  The opportunity to clarify any issues or questions
from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

John C. Norvell, Ph.D.
Division of Cell Biology and Biophysics
National Institute of General Medical Sciences
45 Center Drive, Room 2AS.13B
Bethesda, MD  20892-6200
Telephone:  (301) 594-0533
FAX:  (301) 480-2004
Email:  norvellj@nigms.nih.gov

Abraham Levy, Ph.D.
Biomedical Technology
National Center for Research Resources
6705 Rockledge Drive, Room 6150
Bethesda, MD  20892-7965
Telephone:  (301) 435-0755
FAX:  (301) 480-3659
Email:  al26y@nih.gov

Jose Velazquez, Ph.D.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233
Research Triangle Park, NC  27709
Telephone:  (919) 541-4998
FAX:  (919) 451-4998
Email:  Valazqu1@niehs.nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Phyllis Finch-Smith
Grants Management Office
National Institute of General Medical Sciences
45 Center Drive, Room 2AS.55H
Bethesda, MD  20892-6200
Telephone:  (301) 594-5243
FAX:  (301) 480-2554
Email:  finchp@nigms.nih.gov

Ms. Mary Niemiec
Office of Grants and Contracts Management
National Center for Research Resources
6705 Rockledge Drive, Room 6086
Bethesda, MD  20892-7965
Telephone:  (301) 435-0842
FAX:  (301) 480-3777
Email:  mn20z@nih.gov

Mr. Dave Mineo
Chief, Grants Management Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233
Research Triangle Park,  NC 27709
Telephone:  (919) 541-1373
FAX:  (919) 541-2860
Email:  mineo@niehs.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.821 for NIGMS; No. 93.371 for NCRR; and Nos. 93.113 and 93.114 for NIEHS. 
Awards are made under authorization of the Public Health Service Act, Title
IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and
285) and administered under NIH Grants Policy Statement (October 1, 1998) and
Federal Regulations 42 CFR 52 and 45 CFR Part 74.  This program is not subject
to the intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.

The PHS strongly encourages all grant and contract recipients to provide a
smoke-free workplace and promote the non-use of all tobacco products.  In
addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking
in certain facilities (or in some cases, and portion of a facility) in which
regular or routine education, library, day care, health care or early
childhood development services are provided to children.  This is consistent
with the PHS mission to protect and advance the physical and mental health of
the American people.

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